Protein phosphatase-1 (PP1), is a major serine/threonine phosphatase in the mammalian synapse and has been implicated in the control of long-term potentiation (LTP) and long-term depression (LTD) in the hippocamapal neurons, extensively studied models for learning and memory. PP1 association with the actin cytoskeleton underlying postsynaptic membranes is mediated by two isoforms of neuronal-actin-binding proteins (neurabins) that also bind PP1. This positions PP1 to respond rapidly to receptor activation and regulate postsynaptic substrates involved in plasticity. Disruption of the mouse neurabin II gene abolished LTD and PP1 regulation of glutamate receptors but increased the formation of filopodia and spines, which are also required for strengthening and elaborating neural circuits during learning and memory. Our preliminary studies suggest that PP1 recruitment to the neuron-specific isoform, neurabin I, represents a mechanism for inducing filopodia formation. The aims of this proposal is the (1) delineate the molecular basis for PP1 recruitment and regulation by neurabin I; (2) establish the role of neurabin I in the antagonism between PP1 and the growth-factor-activated kinase, p70 s6 kinase, which binds to an adjacent site on neurabin I and inhibits neurite extension; and finally (3) define the physiological importance of recruiting the known PP1 regulator, inhibitor-2, to neurabin I, it role in stabilizing PP1 association with neurabin I and the impact of I-2 phosphorylation-dephosphorylation in regulating the neurabin I-bound phosphatase. Together, these studies will define the importance of neurabin I in PP1 signaling at the actin cytoskeleton and its role in the signal transduction pathways that regulate synaptic plasticity. Elucidating neurabin-mediated PP1 signaling may define the defects in plasticity that contribute to mental retardation, epilepsy and neurodegenerative disease.